Oncotarget

Research Papers:

KDM1 is a novel therapeutic target for the treatment of gliomas

Gangadhara R Sareddy, Binoj C. Nair, Samaya K Krishnan, Vijay K Gonugunta, Quan-guang Zhang, Naoki Miyata, Takayoshi Suzuki, Andrew Brenner, Darrell W Brann and Ratna K Vadlamudi _

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Oncotarget. 2013; 4:18-28. https://doi.org/10.18632/oncotarget.725

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Abstract

Gangadhara R. Sareddy1, Binoj C. Nair1, Samaya K. Krishnan1, Vijay K. Gonugunta1, Quan-guang Zhang2, Takayoshi Suzuki3,4, Naoki Miyata5, Andrew J. Brenner6,7, Darrell W. Brann2 and Ratna K. Vadlamudi1,7

1 The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX

2 Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA

3 Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto, Japan

4 PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, Japan

5 Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi, Japan

6 Department of Hematology and Medical oncology, University of Texas Health Science Center at San Antonio, San Antonio TX

7 Department of Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio TX

Correspondence:

Ratna K. Vadlamudi, email:

Gangadhara R. Sareddy, email:

Keywords: KDM1, p53, Gliomas, GBM, epigenetics

Received: October 26, 2012, Accepted: November 15, 2012, Published: November 17, 2012

Abstract

Glioma development is a multistep process, involving alterations in genetic and epigenetic mechanisms. Understanding the mechanisms and enzymes that promote epigenetic changes in gliomas are urgently needed to identify novel therapeutic targets. We examined the role of histone demethylase KDM1 in glioma progression. KDM1 was overexpressed in gliomas and its expression positively correlated with histological malignancy. Knockdown of KDM1 expression or its pharmacological inhibition using pargyline or NCL-1 significantly reduced the proliferation of glioma cells. Inhibition of KDM1 promoted up regulation of the p53 target genes p21 and PUMA. Patient-derived primary GBM cells expressed high levels of KDM1 and pharmacological inhibition of KDM1 decreased their proliferation. Further, KDM1 inhibition reduced the expression of stemness markers CD133 and nestin in GBM cells. Mouse xenograft assays revealed that inhibition of KDM1 significantly reduced glioma xenograft tumor growth. Inhibition of KDM1 increased levels of H3K4-me2 and H3K9-Ac histone modifications, reduced H3K9-me2 modification and promoted expression of p53 target genes (p21 and PUMA), leading to apoptosis of glioma xenograft tumors. Our results suggest that KDM1 is overexpressed in gliomas and could be a potential therapeutic target for the treatment of gliomas.


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